Altered Cl − homeostasis hinders forebrain GABAergic interneuron migration in a mouse model of intellectual disability | Zendy

Andrea Maset | Zendy; Luisa Galla | Zendy; Simona Francia | Zendy; Olga Cozzolino | Zendy; Paola Capasso | Zendy; Rosa Chiara Goisis | Zendy; Gabriele Losi | Zendy; Angelo Lombardo | Zendy; Gian Michele Ratto | Zendy; Claudia Lodovichi | Zendy

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Altered Cl ⁻ homeostasis hinders forebrain GABAergic interneuron migration in a mouse model of intellectual disability

Author(s) -

Andrea Maset,

Luisa Galla,

Simona Francia,

Olga Cozzolino,

Paola Capasso,

Rosa Chiara Goisis,

Gabriele Losi,

Angelo Lombardo,

Gian Michele Ratto,

Claudia Lodovichi

Publication year - 2020

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.2016034118

Subject(s) - forebrain , gabaergic , neuroscience , intellectual disability , inhibitory postsynaptic potential , biology , interneuron , mutation , central nervous system , genetics , gene

Impairments of inhibitory circuits are at the basis of most, if not all, cognitive deficits. The impact of OPHN1, a gene associate with intellectual disability (ID), on inhibitory neurons remains elusive. We addressed this issue by analyzing the postnatal migration of inhibitory interneurons derived from the subventricular zone in a validated mouse model of ID (OPHN1 -/y mice). We found that the speed and directionality of migrating neuroblasts were deeply perturbed in OPHN1 -/y mice. The significant reduction in speed was due to altered chloride (Cl - ) homeostasis, while the overactivation of the OPHN1 downstream signaling pathway, RhoA kinase (ROCK), caused abnormalities in the directionality of the neuroblast progression in mutants. Blocking the cation-Cl - cotransporter KCC2 almost completely rescued the migration speed while proper directionality was restored upon ROCK inhibition. Our data unveil a strong impact of OPHN1 on GABAergic inhibitory interneurons and identify putative targets for successful therapeutic approaches.

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